Despite advances in the management of the septic patient, a large number of such patients die of the ensuing septic shock and mutiple organ failure. The high mortality rate may be reduced by modulation of the mediators responsible for progressive cell and organ dysfunction in sepsis. Although apoptosis plays an important role in the pathophysiology of sepsis, the regulation of apoptotic cell clearance in sepsis is not fully understood. Recent evidence showed that the opsonizing protein milk fat globule epidermal growth factor- factor VIII (MFG-E8) is involved in apoptotic cell clearance. We have discovered that the spleen appears to be the major source of MFG-E8 production and MFG-E8 is downregulated in sepsis. The lack of MFG-E8 is responsible for the reduced clearance of apoptotic cells in sepsis since administration of MFG-E8-containing exosomes (generated from bone marrow dendritic cells) or recombinant MFG-E8 increases phagocytosis of apoptotic cells. In addition, MFG-E8-containing exosomes or recombinant MFG-E8 reduce inflammatory cytokines and improve survival in sepsis. The biological effect of this molecule has been confirmed by using the MFG-E8 knockout animal model. MFG-E8's direct anti-inflammatory activity appears to be mediated by the inhibition of NF-kappaB and mitogen-activated protein kinase (p38, JNK, ERK) signaling pathways. These findings lead us to propose a novel concept that the enhancement of apoptotic cell clearance via MFG-E8-mediated mechanisms is protective in sepsis. Thus, we hypothesize that the decreased MFG-E8 expression plays an important role in reducing apoptotic cell clearance in sepsis. We further hypothesize that the beneficial effect of MFG-E8 in sepsis is mediated not only by the enhancement of apoptotic cell clearance (primary mechanism), but also by the direct reduction of proinflammatory cytokines (secondary mechanism). The proposed studies will 1) further confirm the role of MFG-E8 downregulation in producing the decreased apoptotic cell clearance in sepsis; 2) determine the optimal dosage of recombinant MFG-E8 in maintaining organ function and reducing mortality in sepsis; and 3) elucidate the direct anti-inflammatory mechanism responsible for the beneficial effect of MFG-E8 in sepsis. The proposed studies will provide novel information about mechanisms responsible for sepsis-induced impairment of apoptotic cell clearance, and identify a new therapeutic approach to maintain organ function and reduce late mortality in sepsis.